Research Article

Kidney Blood Press Res Received: January 27, 2021

Accepted: June 2, 2021
DOI: 10.1159/000517581 Published online: July 27, 2021

The Risk Factors and Clinical Outcomes

Associated with Acute Kidney Injury in Patients
with COVID-19: Data from a Large Cohort in Iran
Hormat Rahimzadeh a Sina Kazemian b Maryam Rahbar a
     

Hossein Farrokhpour b Mahnaz Montazeri c Samira Kafan d

     

Ahmad Salimzadeh e Mohammad Talebpour f Fazeleh Majidi g

     

Atefeh Jannatalipour g Effat Razeghi a, h
   

aDepartment of Nephrology Diseases, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran;
bStudents’
Scientific Research Center (SSRC), Tehran University of Medical Sciences, Tehran, Iran; cDepartment of
Infectious Diseases, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran; dDepartment of Pulmonary
Diseases, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran; eRheumatology Research Center,
Sina Hospital, Tehran University of Medical Science, Tehran, Iran; fDepartment of Surgery, Sina Hospital, Tehran
University of Medical Sciences, Tehran, Iran; gResearch Development Center, Sina Hospital, Tehran University of
Medical Sciences, Tehran, Iran; hNephrology Research Center, Center of Excellence in Nephrology, Tehran University
of Medical Sciences, Tehran, Iran

Keywords
Acute kidney injury · COVID-19 · Mortality · Risk factors ·
SARS-CoV-2
Abstract
Introduction: Kidney involvement, ranging from mild hema-
turia and proteinuria to acute kidney injury (AKI) in patients
with coronavirus disease-2019 (COVID-19), is a recent find-
ing with various incidence rates reported among hospital-
ized patients with COVID-19. Given the various AKI rates and
their associated risk factors, lack of AKI recovery in the major-
ity of patients hospitalized with COVID-19, and limited data
regarding AKI in patients with COVID-19 in Iran, we aim to
investigate the potential risk factors for AKI development
and its incidence in patients hospitalized with COVID-19.
Methods: In this retrospective cohort study, we enrolled
adult patients referred to the Sina Hospital, Iran, from Febru-
ary 20 to May 14, 2020, with either a positive PCR test or a
highly susceptible chest computed tomography features
consistent with COVID-19 diagnosis. AKI was defined accord-
ing to the kidney disease improving global outcomes crite-
ria, and patients were stratified based on their AKI staging.
We evaluated the risk indicators associated with AKI during
hospitalization besides in-hospital outcomes and recovery
rate at the time of discharge. Results: We evaluated 516 pa-
tients with a mean age of 57.6 ± 16.1 years and a male-to-
female ratio of 1.69 who were admitted with the COVID-19
diagnosis. AKI development was observed among 194
(37.6%) patients, comprising 61.9% patients in stage 1, 18.0%
in stage 2, and 20.1% in stage 3. Out of all patients, AKI oc-
curred in 58 (11.2%) patients during the hospital course, and
136 (26.3%) patients arrived with AKI upon admission. AKI
development was positively associated with all of the in-hos-

karger@karger.com © 2021 The Author(s) Correspondence to:

www.karger.com/kbr Published by S. Karger AG, Basel Hossein Farrokhpour, hosseinfarrokhpour7 @ gmail.com
This is an Open Access article licensed under the Creative Commons
Effat Razeghi, razeghia @ tums.ac.ir
Attribution-NonCommercial-4.0 International License (CC BY-NC)
(http://www.karger.com/Services/OpenAccessLicense), applicable to
the online version of the article only. Usage and distribution for com-
mercial purposes requires written permission.
pital outcomes, including intensive care unit admissions,
need for invasive ventilation, acute respiratory distress syn-
drome (ARDS), acute cardiac injury, acute liver injury, multi-
organ damage, and mortality. Patients with stage 3 AKI
showed a significantly higher mortality rate, ARDS, and need
for invasive ventilation than other stages. After multivariable
analysis, male sex (odds ratio [OR]: 11.27), chronic kidney dis-
ease (CKD) (OR: 6.89), history of hypertension (OR: 1.69), dis-
ease severity (OR: 2.27), and high urea levels (OR: 1.04) on
admission were independent risk indicators of AKI develop-
ment. Among 117 (28.1%) patients who experienced AKI and
survived, only 33 (28.2%) patients made a recovery from the
AKI, and 84 (71.8%) patients did not exhibit full recovery at
the time of discharge. Discussion/Conclusion: We found
that male sex, history of CKD, hypertension, disease severity,
and high serum urea were independent risk factors associ-
ated with AKI in patients with COVID-19. Also, higher stages
of AKI were associated with increased risk of mortality and
in-hospital complications. Our results indicate a necessity for
more precise care and monitoring for AKI during hospitaliza-
tion in patients with COVID-19, and lack of AKI recovery at
the time of discharge is a common complication in such pa-
tients. © 2021 The Author(s)
Published by S. Karger AG, Basel
Introduction
Coronavirus disease-2019 (COVID-19) was first iden-
tified as a series of pneumonia cases with unknown origin
in China, Hubei Province, in December 2019 [1]. World
Health Organization declared the novel disease as pan-
demic due to rapid spreading and high transmission rate
on March 11, 2020. The disease is caused by acute respi-
ratory syndrome coronavirus 2 (SARS-CoV-2) with clin-
ical features ranging from mild self-limiting respiratory
tract infection or mild respiratory symptoms to severe
acute respiratory distress syndrome (ARDS) and multi-
organ failure and finally death [1]. Kidney involvement,
including acute kidney injury (AKI), proteinuria, and he-
maturia, has been a recent finding among patients hospi-
talized with COVID-19 [2–4]. AKI is one of the most se-
vere types of kidney involvement reported at various rates
from 0.5% to as high as 50% in multiple studies in differ-
ent countries [1, 3–17], and is considered a prognostic
factor impacting both severity and mortality [1, 15, 16].
Many pathophysiological pathways have been suggested
for kidney abnormality in COVID-19 patients, including
direct invasion and cytotoxic effect of the virus on kid-
neys leading to acute tubular necrosis supported by evi-
2 Kidney Blood Press Res
DOI: 10.1159/000517581
dence of SARS-CoV-2 in kidney biopsy and urinary de-
tection. Other mechanisms that accounted for kidney in-
jury are prothrombotic state, hemodynamic instability,
and cytokine storm [18–22]. Differences in study popula-
tions and comorbidities of patients, besides different ad-
mission guidelines and criteria used for AKI definition,
can partially explain the various AKI rates reported [11].
Accordingly, in this retrospective cohort study conducted
at Sina Hospital, Iran, we aim to investigate the potential
risk factors for AKI development and its incidence in pa-
tients hospitalized with COVID-19 to develop more ap-
propriate preventive measures.
Material and Methods
Statement of Ethics
Our study’s protocol is in line with the 2013 Helsinki declara-
tion and approved by the Ethics Committee of Tehran University
of Medical Sciences (IR.TUMS.VCR.REC.1399.005). All partici-
pants or their legal guardians gave written informed consent be-
fore inclusion in the study.
Study Design
In this cohort study, we retrospectively enrolled 611 patients
≥18 years old who were admitted to Sina Hospital, a tertiary edu-
cational center designated for patients with COVID-19 by the
government, affiliated with Tehran University of Medical Scienc-
es from February 20 to May 14, 2020. Patients with a history of
hemodialysis or end-stage renal disease prior to the hospitaliza-
tion were excluded. We used electronic medical records from each
individual to obtain personal data, including demographic char-
acteristics, past medical history, admission vital signs, laboratory
parameters, and in-hospital outcomes and complications. The
treatment used for patients mainly included antiviral agents (os-
eltamivir, lopinavir + ritonavir, interferon beta 1a, favipiravir, and
umifenovir) and corticosteroids (dexamethasone, methylprednis-
olone, prednisolone, and hydrocortisone), according to the at-
tending physician’s discretion, based on national guideline pub-
lished for standard care in patients with COVID-19 [23]. Besides,
anticoagulant (enoxaparin sodium, heparin) was also used in pa-
tients determined to be at high risk for thromboembolic events
(23). The further details of patient care for individuals presenting
with respiratory symptoms to Sina Hospital emergency depart-
ment have been published previously [24].
Since there were no prior records of baseline serum creatinine
(SCr) available in most patients, baseline SCr for each individual
was imputed based upon a modification of diet in renal disease
(MDRD) estimated glomerular filtration fraction of 75 mL/
min/1.73 m2 as per the kidney disease: Improving global outcomes
(KDIGO) AKI guidelines [25]. The formula used to determine
baseline serum creatinine was adopted with regard to Závada et al.
[26], with the formula displayed in online suppl. Table 1 (see www.
karger.com/doi/10.1159/000517581 for all online suppl. material).
COVID-19 diagnosis was defined as any of the following: (1)
Positive real-time reverse-transcriptase polymerase chain reaction
(PCR) test of oropharyngeal, nasopharyngeal, or endotracheal
Rahimzadeh et al.
swab specimens or (2) patients with high susceptibility according
to the World Health Organization’s interim guidance and Iranian
national committee of COVID-19, including patients with ground-
glass opacity alone or ground-glass opacity accompanied with con-
solidation in chest computed tomography, not entirely explained
by lobar collapse, volume overload, or nodules in company with
the history compatible with COVID-19 [27–30]. We excluded 88
patients due to lack of key information regarding their medical
records or lack of laboratory data. Also, 7 patients were excluded
due to prior history of end-stage renal disease, and 516 patients
entered the final analysis.
Definitions
AKI was defined according to the KDIGO criteria as any of the
following: (1) Increase in serum creatinine (SCr) to ≥1.5 times to
1.9 times of baseline occurred within the previous 7 days or an in-
crease in SCr by ≥0.3 mg/dL (≥26.5 μmol/L) within 48 h as stage
1, 2–2.9 times increase in serum creatinine within 7 days as stage
2, and 3 times or more increase in serum creatinine within 7 days
as stage 3 (criteria for urine volume <0.5 mL/kg/h for 6 h was ex-
cluded since there were no records of patients’ urine volume in
electronic health data) [25]. AKI recovery was determined as <0.3
mg/dL (<26.5 μmol/L) difference from the baseline serum creati-
nine and with less than 50% increase from the baseline creatinine
at the time of discharge [6, 31].
Cardiac disease was described as a history of coronary artery
disease (≥50% stenosis in coronary arteries) or heart failure, or
previous treatment for conditions named. History of stroke or
transient ischemic attack was defined as cerebrovascular disease.
Patients with a history of interstitial lung disease, asthma, or
chronic obstructive pulmonary disease were identified as chronic
lung disease. Chronic kidney disease (CKD) was defined as a glo-
merular filtration rate below 60 mL/min or need for renal replace-
ment therapy. Patients with a history of neoplasm are considered
positive for malignancy. ARDS was defined according to the Ber-
lin definition criteria [32]. Acute cardiac injury (ACI) was identi-
fied if the serum level of high-sensitive cardiac troponin I was
above the 99th percentile upper reference limit (11 pg/mL for
women and 26 pg/mL for men) [33]. An increase in serum levels
of alanine aminotransferase or aspartate aminotransferase more
than 3 units above upper limit normal or alkaline phosphatase or
total bilirubin more than 2 times of upper limit normal was diag-
nosed as acute liver injury (ALI) [34]. The neutrophil-to-lympho-
cyte ratio (NLR) was computed by dividing the absolute neutro-
phil count by the lymphocyte count. The platelet-to-lymphocyte
ratio was calculated by dividing the absolute platelet count by the
lymphocyte count. The systemic immune-inflammation index
was measured by (neutrophil count × platelets)/(lymphocyte
count). Patients with any of the following conditions were consid-
ered to have a severe disease: Oxygen saturation ≤93%, or >50%
of lung involvement in chest computed tomography scan, dys-
pnea, septic shock, respiratory failure, or multiple organ dysfunc-
tion/failure. The remaining patients were categorized as nonse-
vere COVID-19. These criteria were defined in line with Wu and
colleague’s study and were modified to compare patients with se-
vere COVID-19 to nonsevere patients in our study [35]. Multiple
organ damage was determined as patients with at least 2 compli-
cations, including ARDS, ACI, AKI, or ALI. Positive drug history
was considered as taking medication for at least 1 month before
admission.
Risk Factors and Clinical Outcomes
Associated with AKI in COVID-19 Patients
Statistical Analysis
Categorical variables were expressed as numbers and percent-
ages (%) and analyzed using Fisher’s exact test and χ2 test. Distri-
bution in continuous variables was checked based on the Kol-
mogorov-Smirnov and Shapiro-Wilk normality tests, P-P plot,
and histogram to test the population study’s normality. Continu-
ous variables with normal distribution were presented as mean ±
standard deviation and analyzed using independent samples t test.
On the other hand, variables without normal distribution were re-
ported as median (interquartile range) and were analyzed using the
Mann-Whitney U test. Binary logistic regression analysis was used
to evaluate the independent indicators associated with AKI inci-
dence during hospitalization. Variables with p < 0.05 in univariant
regression were enrolled in multivariant regression analysis as pos-
sible risk indicators (including age, male sex, disease severity, his-
tory of hypertension, diabetes mellitus [DM], cardiac disease,
CKD, taking angiotensin-converting enzyme inhibitor [ACEI] or
angiotensin II receptor blocker [ARB] medications, NLR, urea,
and C-reactive protein [CRP] levels on admission). For statistical
analysis, we used the SPSS 22 software for Windows (Chicago, IL,
USA).
Results
Baseline Characteristics of Patients
A total of 611 patients were admitted to the Sina Hos-
pital from February 20 to May 14, 2020, with the impres-
sion of COVID-19, which were confirmed later based on
positive PCR swab test or clinical criteria defined. After
excluding 95 patients, 516 patients entered the final anal-
ysis. The mean age was 57.6 ± 16.1 years, 62.8% were
male, 360 (69.8%) patients incurred severe COVID-19,
and 79 (15.3%) patients were admitted to the ICU at some
point during their hospitalization. The mortality rate for
the whole cohort was 19.4% (100 out of 516).
During this study, 194 (37.6%) patients developed AKI
either on admission or during the hospital course. AKI
occurred in 58 (11.2%) patients during the hospital
course. In addition, there were 136 (26.3%) patients with
AKI diagnosis upon admission, of whom 47 (34%) pa-
tients also had increased creatinine values during hospi-
talization. AKI staging was determined following KDIGO
criteria, and 120 (61.9%) patients were categorized in
stage 1, 35 (18.0%) patients in stage 2, and 39 (20.1%) pa-
tients in stage 3.
Although all of the included patients were highly sus-
picious for COVID-19 based on the national and inter-
national guidelines [36, 37], 289 (56.0%) patients under-
went swab PCR test, of whom 131 (45.3%) were positive
for COVID-19. Out of all patients with AKI (N = 194),
a swab PCR test was done in 122 (62.9%) patients, with
56 (45.9%) specimens reported positive. The AKI inci-
Kidney Blood Press Res 3
DOI: 10.1159/000517581
Table 1. Baseline characteristics and in-hospital outcomes of COVID-19 patients with and without AKI

Characteristic† Total (N = 516) AKI (N = 194) Non-AKI (N = 322) p*

Demographics
Age, year 57.6±16.1 60.6±17.5 55.8±14.9 0.002
Sex
Female 192 (37.2) 29 (14.9) 163 (50.6) <0.001
Male 324 (62.8) 165 (85.1) 159 (49.4)
BMI, kg/m2 27.5±4.6 27.1±4.2 27.7±4.9 0.346
Comorbidities
Hypertension 213 (41.3) 104 (53.6) 109 (33.9) <0.001
DM 166 (32.2) 82 (42.3) 84 (26.1) <0.001
Cardiac disease 114 (22.1) 57 (29.4) 57 (17.7) 0.002
Cerebrovascular disease 18 (3.5) 12 (6.2) 6 (1.9) 0.013
Chronic lung disease 38 (7.4) 16 (8.2) 22 (6.8) 0.603
Malignancy 18 (3.5) 11 (5.7) 7 (2.2) 0.047
CKD 20 (3.9) 17 (8.8) 3 (0.9) <0.001
Kidney transplant history 5 (1.0) 5 (2.6) 0 (0.0) 0.007
Drug history
ACEI or ARB 101 (19.6) 55 (28.4) 46 (14.3) <0.001
Vital signs on admission
Heart rate 88.2±16.5 88.9±18.9 87.1±14.6 0.099
SBP, mm Hg 123.7±20.0 122.9±19.6 124.2±20.4 0.545
DBP, mm Hg 75.6±11.6 75.1±10.8 76.0±12.1 0.435
Respiratory rate 20.7±8.8 22.6±12.5 19.5±5.2 0.010
Temperature, oC 37.2±0.9 37.2±0.9 37.2±0.9 0.897
Oxygen saturation, 90.4±7.6 89.4±8.6 91.0±6.9 0.028
Laboratory data on admission
WBC, ×109/L 6.5 (5.1–9.3) 6.7 (5.3–10.4) 6.2 (5.0–8.6) 0.009
Neutrophil, ×109/L 4.6 (3.4–7.2) 5.1 (3.8–8.2) 4.5 (3.3–6.6) 0.001
Lymphocyte, ×109/L 1.2 (0.9–1.7) 1.1 (0.8–1.5) 1.3 (0.9–1.8) <0.001
Platelets, ×109/L 189.0 (149.2–251.7) 178.0 (144.0–231.2) 196.5 (151.0–260.2) 0.010
Neutrophil-to-lymphocyte ratio 3.8 (2.5–6.3) 4.8 (2.9–9.0) 3.5 (2.2–5.2) <0.001
Platelet-to-lymphocyte ratio 156.2 (115.0–213.0) 157.8 (115.2–238.6) 153.4 (114.3–204.2) 0.115
SII 752.8 (444.4–1,320.3) 880.0 (492.6–1,734.2) 734.9 (392.1–1,148.7) 0.001
RBC, ×1012/L 4.7 (4.2–5.1) 4.8 (4.0–5.2) 4.6 (4.3–5.0) 0.312
Hemoglobin, g/dL 13.7 (12.4–15.1) 13.9 (12.3–15.3) 13.6 (12.4–15.0) 0.351
Urea, mg/dL 30.5 (22.2–46.0) 44.0 (30.0–74.2) 26.0 (20.0–35.0) <0.001
BUN/creatinine ratio 15.1 (11.2–25.8) 17.6 (12.0–43.1) 13.5 (9.8–21.9) <0.001
Creatinine, mg/dL 1.05 (0.89–1.27) 1.34 (1.17–1.77) 0.94 (0.84–1.08) <0.001
GFR, mL/min 66.65 (53.41–79.48) 53.48 (35.70–68.25) 72.18 (62.63–83.79) <0.001
Baseline serum creatinine** 0.95 (0.89–1.21) 0.93 (0.88–0.98) 1.03 (0.90–1.24) <0.001
Discharge creatinine 1.07 (0.90.1.35) 1.40 (1.16–2.11) 0.95 (0.85–1.08) <0.001
Sodium, mmol/L 135.7 (132.4–138.8) 135.3 (132.1–139.0) 135.8 (132.7–138.7) 0.633
Potassium, mmol/L 4.2 (3.9–4.6) 4.3 (4.0–4.7) 4.1 (3.8–4.5) <0.001
Calcium, mmol/L 8.6 (8.2–9.0) 8.6 (8.0–9.0) 8.7 (8.3–9.1) 0.017
Phosphorus, mmol/L 3.3 (2.9–3.9) 3.4 (2.9–4.1) 3.3 (2.9–3.8) 0.153
Magnesium, mmol/L 2.2 (2.0–2.5) 2.2 (2.0–2.5) 2.2 (2.0–2.5) 0.657
CRP, mg/L 57.1 (21.2–104.0) 69.4 (37.5–125.3) 47.4 (16.7–85.3) <0.001
ESR, mm/h 44.0 (25.5–74.0) 46.0 (26.0–75.0) 41.0 (24.2–71.0) 0.400
LDH, U/L 532.0 (431.5–698.5) 572.0 (467.5–772.0) 523.5 (415.7–668.7) 0.005
hs-cTnI, pg/mL 6.0 (1.5–18.7) 10.3 (3.1–40.0) 4.3 (1.5–9.9) <0.001
AST, U/L 50.0 (38.0–68.2) 60.0 (41.0–79.0) 46.0 (37.0–59.0) <0.001
ALT, U/L 36.0 (27.0–51.0) 40.0 (32.0–58.0) 34.0 (25.0–48.0) <0.001
ALP, U/L 166.0 (128.0–214.0) 166.0 (127.0–213.5) 167.0 (129.0–214.0) 0.760
In-hospital outcomes
Hospital length of stay, day 4.0 (2.0–7.0) 5.0 (3.0–9.0) 4.0 (2.0–6.0) <0.001
ICU admission 79 (15.3) 55 (28.4) 24 (7.5) <0.001
Severity 360 (69.8) 151 (77.8) 209 (64.9) 0.002
Mortality 100 (19.4) 77 (39.7) 23 (7.1) <0.001
ARDS 161 (31.3) 78 (40.4) 83 (25.8) 0.001
Invasive ventilation 68 (13.2) 54 (27.8) 14 (4.3) <0.001
ACI 111 (21.5) 61 (31.4) 50 (15.5) <0.001
ALI 54 (10.5) 29 (14.9) 25 (7.8) 0.010
Multiorgan damage 139 (26.9) 109 (55.2) 30 (9.3) <0.001

ACEI, angiotensin-converting enzyme inhibitor; ACI, acute cardiac injury; AKI, acute kidney injury; ALI, acute liver injury; ALP, alkaline phosphatase;
ALT, alanine transaminase; ARB, angiotensin II, receptor blocker; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; BMI, body
mass index; BUN, blood urea nitrogen; CKD, chronic kidney disease; CRP, C-reactive protein; DBP, diastolic blood pressure; DM, diabetes mellitus; ESR,
erythrocyte sedimentation rate; GFR, glomerular filtration rate; hs-cTnI, high-sensitive cardiac troponin I; LDH, lactate dehydrogenase; RBC, red blood cell;
SBP, systolic blood pressure; SII, systemic immune-inflammation index; WBC, white blood cell. † Data are presented as mean±standard deviation, number
(%), or median (interquartile range). * Statistically significant p values are bolded. ** Based on MDRD calculation formula (eGFR = 75 mL/min/1.73 m2).

4 Kidney Blood Press Res Rahimzadeh et al.

DOI: 10.1159/000517581
Table 2. In-hospital outcomes according to different stages of AKI by the KDIGO in patients with COVID-19
In-hospital outcome† AKI (N = 194) Stage 1 (N = 120)
Mortality 77 (39.7) 27 (22.5)**
Severity 151 (77.8) 87 (72.5)
ARDS 78 (40.4) 39 (32.8)**
Invasive ventilation 54 (27.8) 20 (16.7)**
ACI 61 (31.4) 30 (25.0)
ALI 29 (14.9) 11 (9.2)**
Multiorgan damage 109 (56.2) 54 (45.0)**
ACI, acute cardiac injury; AKI, acute kidney injury; ALI, acute liver injury; ARDS, acute respiratory distress syndrome. † Data are
presented as number (%). * Statistically significant p values are bolded. ** Statistically significant Bonferroni-adjusted p values (p <
0.0083).
dence rate in patients with a positive PCR test was 42.7%
(56 out of 131 patients), similar to the whole cohort re-
sults.
Baseline characteristics of patients are presented in
Table 1. Patients who developed AKI were more likely to
be older, male, and with more underlying diseases except
for chronic lung disease compared to patients without
AKI. About 59.9% of patients were reported to have at
least 1 comorbidity, and the most prevalent comorbidi-
ties were hypertension (41.3%), DM (32.2%), and cardiac
disease (22.1%). Out of 194 patients with AKI, 151 (77.8%)
patients had a severe form of COVID-19, and 54 (27.8%)
patients needed invasive ventilation. The ICU admission
and mortality rate were significantly higher in the AKI
group than the non-AKI group (28.4% vs. 7.5%, p value
<0.001, 39.7% vs. 7.1%, p value <0.001, respectively). We
also stratified patients based on their AKI staging into 3
groups and performed subgroup analysis (online suppl.
Table 1). Patients who reached higher AKI stages were
more likely to be older and have DM, CKD, and malig-
nancy as their past medical history and take ACEI or ARB
medications before admission.
There was no significant difference in vital signs on
admission between the 2 groups except for lower oxygen
saturation and higher respiratory rate on admission in
patients with AKI. In terms of laboratory data, white
blood cells, neutrophil count, NLR, systemic immune-in-
flammation index, urea, potassium, calcium, CRP, LDH,
high-sensitive cardiac troponin I, aspartate aminotrans-
ferase, and alanine aminotransferase were significantly
higher in patients with the development of AKI.
During this study, 161 patients underwent urine anal-
ysis test comprising 84 (52.1%) patients with no protein-
uria, and trace or mild (1+), moderate (2+), and severe
(3+ and 4+) reported in 38 (23.6%), 20 (12.4%), and 19
Risk Factors and Clinical Outcomes
Associated with AKI in COVID-19 Patients
Stage 2 (N = 35) Stage 3 (N = 39) p value*
18 (51.4) 32 (82.1)** <0.001
29 (82.9) 35 (89.7) 0.058
15 (42.9) 24 (61.5)** 0.006
12 (34.3) 22 (56.4)** <0.001
15 (42.9) 16 (41.0) 0.048
9 (25.7) 9 (23.1) 0.015
26 (74.3) 29 (74.4) <0.001
(11.8%) patients, respectively. There was a significant dif-
ference in proteinuria incidence in patients who devel-
oped AKI compared to non-AKI patients (63.9% vs.
29.3%, p value: <0.001). Among patients with AKI, 86
(44.3%) patients had records of urine analysis tests avail-
able, with 29 (33.7%) of them reported as mild protein-
uria, 13 (15.1%) with moderate, and 13 (15.1%) with se-
vere proteinuria and 31 (36.1%) patients with no protein-
uria exhibited in urine analysis.
Based on the final status of discharge or mortality,
among 117 (28.1%) patients who experienced AKI and
survived, 33 (28.2%) patients made a recovery from the
AKI, and 84 (71.8%) patients did not fully recover at the
time of discharge. Deceased patients exhibited similar re-
covery rates (15/77 [19.5%] patients were recovered from
AKI), indicating no difference in recovery rate between
the discharged and deceased groups (28.2% vs. 19.5%, re-
spectively, p value = 0.168).
AKI Staging and In-Hospital Outcomes
AKI development was positively associated with all of
the in-hospital outcomes, including ICU admissions,
need for invasive ventilation, ARDS, ACI, ALI, multior-
gan damage, and mortality. Moreover, we evaluated the
in-hospital outcomes according to the patients’ AKI stag-
ing (Table 2). All in-hospital outcomes increased in high-
er stages of AKI, with a statistically significant difference
among the 3 stages except for disease severity (p value:
0.058). Patients with stage 1 AKI had a significantly low-
er mortality rate (22.5%), ARDS, need for invasive venti-
lation, ALI, and multiorgan damage compared to other
groups. On the other hand, patients with stage 3 AKI had
a significantly higher mortality rate (71.1%), ARDS
(61.5%), and a need for invasive ventilation (56.4%) (Ta-
ble 2).
Kidney Blood Press Res 5
DOI: 10.1159/000517581
 Table 3. Logistic regression analysis for risk indicators of AKI development during hospitalization in patients
with COVID-19

Model 1† Model 2‡
odds ratio 95% CI p value* odds ratio 95% CI p value*

Age 1.02 1.01–1.03 0.001

Male sex 5.83 3.71–9.16 <0.001 11.27 5.97–21.26 <0.001
Severity 1.90 1.26–2.86 0.002 2.27 1.35–3.83 0.002
Hypertension 2.26 1.57–3.25 <0.001 1.69 1.03–2.79 0.039
DM 2.07 1.42–3.03 <0.001
Cardiac disease 2.04 1.27–3.27 0.003
CKD 10.21 2.95–35.33 <0.001 6.89 1.57–30.18 0.010
ACEI/ARB 2.37 1.53–3.69 <0.001
NLR 1.03 1.00–1.05 0.047
Urea (mg/dL) 1.04 1.03–1.05 <0.001 1.04 1.03–1.05 <0.001
CRP (mg/L) 1.01 1.00–1.01 <0.001

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II, receptor blocker; AKI, acute kidney
injury; CI, confidence interval; CKD, chronic kidney disease; CRP, C-reactive protein; DM, diabetes mellitus;
NLR, neutrophil-to-lymphocyte ratio. * Statistically significant p values are bolded. † Univariate binary logistic
regression. ‡ Multivariate binary logistic regression adjusted for age, sex, hypertension, DM, cardiac disease, CKD,
history of ACEI/ARB, NLR, urea, and CRP.

Predictors of AKI Development
We used univariate logistic regression analysis to iden-
tify the potential risk indicators of AKI development dur-
ing hospitalization, which revealed older age, male sex,
disease severity, history of hypertension, DM, cardiac dis-
ease, CKD, history of treatment with ACEI/ARB medica-
tions, higher NLR, urea, and CRP as potential predictors
of AKI (Table  3). However, after multivariate analysis,
only male sex (odds ratio [OR]: 11.27, 95% confidence
interval [CI]: 5.97–21.26, p value: <0.001), disease sever-
ity (OR: 2.27, 95% CI: 1.35–3.83, p value: 0.002), history
of hypertension (OR: 1.69, 95% CI: 1.03–2.79, p value:
0.039), CKD (OR: 6.89, 95% CI: 1.57–30.18, p value:
0.010), and higher serum urea levels on admission (OR:
1.04, 95% CI: 1.03–1.05, p value <0.001) were indepen-
dently associated with AKI development during hospital-
ization (Table  3). In the sensitivity analysis in patients
with positive PCR test (N = 131), we found disease sever-
ity, male sex, DM, and urea levels on admission as inde-
pendent risk indicators of AKI development during hos-
pitalization (online suppl. Table 2).
Discussion
In this retrospective cohort study, 516 patients with
COVID-19 were evaluated for AKI development. We de-
tected an incidence rate of 37.6% for AKI among all pa-
tients and a similar rate of 42.7% in patients with a positive
PCR test. In the multivariable model, male sex, disease se-
verity, history of CKD, hypertension, and high serum urea
levels on admission were identified as independent risk
indicators of AKI development during hospitalization.
Renal involvement in SARS-CoV-2 and Middle East-
ern respiratory syndrome coronavirus is a common com-
plication with different presentations, including high
rates of proteinuria and hematuria reported [2, 38]. In
addition, patients with COVID-19 seem to have a signif-
icantly higher chance of developing AKI [6, 39]. Despite
the limited number of urine analysis data available in this
study, a substantial number of patients (48.8%) had pro-
teinuria in urine analysis compatible with previous re-
ports [2–4, 15, 40]. Besides, significantly higher protein-
uria values were observed in patients who developed AKI
than in patients who did not suffer from this complica-
tion (65.1% vs. 29.3%, p value: <0.001) [40, 41].
Many pathophysiologic pathways have been suggested
for renal involvement in patients with COVID-19. It has
been demonstrated that SARS-CoV-2 uses the angioten-
sin-converting enzyme 2 (ACE-2) receptor for cell entry
[42–44]. ACE-2 receptors are mainly expressed in lung
cells; however, they function in many other body organs,
including the kidney and gastrointestinal tract, with a
higher expression on the cell membranes [42, 45, 46]. The
presence of SARS-CoV-2 RNA in glomerular cells shown
by Puelles et al. [21] and SARS-CoV-2 detection in kid-

6 Kidney Blood Press Res Rahimzadeh et al.

DOI: 10.1159/000517581
neys and urine of patients with COVID-19 demonstrated
by Cheng et al. [47] could be supportive evidence for di-
rect glomerular damage by the virus. Postmortem exami-
nations of 6 patients with COVID-19 revealed severe
acute tubular necrosis and lymphocyte infiltration accom-
panied by the detection of SARS-CoV-2 antigen in kidney
tubules, suggesting not only direct cytotoxicity but also
tubular injury mediated by complement deposition and
macrophage activation [48]. In another study, Sue et al.
[20] examined 26 postmortem patients with COVID-19
and observed endothelial damage by erythrocyte aggrega-
tion and diffused proximal tubule damage accompanied
by loss of the brush border, corona virus-like particles in
the tubular epithelium, and upregulation of ACE-2 in the
kidney. Other potential factors contributing to the renal
injury include the prothrombotic state induced by the vi-
rus, sepsis, systemic hemodynamic instability, hypox-
emia, and possible drug interactions [4, 49, 50].
Here, we report a 37.6% AKI occurrence, consistent
with 3 studies conducted in the USA and Brazil with
36.6%, 43%, and 50% AKI occurrence rates [6, 11, 17].
Nevertheless, this rate is higher than the largest meta-
analysis performed to date by Fu et al. [15], with the
pooled incidence rate of 28.6% for AKI, reported in hos-
pitalized COVID-19 patients from the USA and Europe.
On the other hand, in previously reported studies in Chi-
na, there was a significantly lower incidence rate of AKI
varying from 0.5% to 29.% [1, 4, 5, 7, 8, 10], and Fu et al.
[15] reported an overall incidence rate of 5.5% for studies
conducted in China. The difference between different
ranges of AKI incidence may be explained by different
population studies and underlying diseases of patients
with COVID-19 in these studies. Our population’s base-
line features in this study were more similar to previous
reports from Europe, the USA, and Brazil. Another expla-
nation for varying ranges of AKI incidence could be dif-
ferent definitions of AKI used in different studies. In
studies carried out in China, baseline SCr is mostly deter-
mined based on patients’ first creatinine record after ad-
mission. However, in reports with higher rates of AKI, the
baseline SCr is calculated according to previous creati-
nine records of patients before hospitalization available
or imputation based on a glomerular filtration rate 75
mL/min/1.73 m2 [6, 11]. Besides the inclusion criteria for
admission, patients’ ethnicity in different countries could
potentially affect patient’s baseline characteristics [16].
In previous studies, older age, male sex, history of CKD,
hypertension, DM, and prior cardiovascular disease have
been suggested as risk factors for AKI [5, 15]. In this study,
after multivariable regression analysis, we found that male
Risk Factors and Clinical Outcomes
Associated with AKI in COVID-19 Patients
sex, disease severity, history of CKD, hypertension, and
high serum urea levels on admission were associated with
a higher risk for AKI development during the hospitaliza-
tion (Table 3). In our subgroups analysis, we found that
patients with higher AKI stages were more likely to be old-
er, with a positive history of hypertension, DM, CKD, ma-
lignancy, and take ACEI or ARB medications before the
hospitalization (online suppl. Table 1). There were also sig-
nificantly higher in-hospital complications such as ARDS,
ACI, ALI, multiorgan damage, and a higher mortality rate,
which indicates the close relationship between higher stag-
es of AKI and poor clinical outcome in line with previous
data reported (Table  2) [11, 16]. Furthermore, patients
with stage 3 AKI showed substantially higher mortality
rates than patients with lower AKI stages, in line with the
study conducted by Zamoner et al. [17] that reported stage
3 AKI as an independent risk factor for mortality in ICU
patients hospitalized with the COVID-19 diagnosis.
Recent studies demonstrated that risk factors associ-
ated with disease severity and COVID-19 mortality were
also associated with increased risk of AKI development in
these patients [1, 11]. In a study by Russo et al. [51], CKD
was reported as a substantial risk factor for AKI, which is
in line with our findings in the current study (OR: 6.89).
Moreover, in keeping with previous findings, hyperten-
sion was identified as a risk indicator of AKI after adjust-
ment [15, 16]. However, DM, previous cardiovascular
disease, obesity, and ACEI/ARB medications which were
previously considered to increase the risk of AKI in pa-
tients with COVID-19 were not identified as independent
risk indicators in this study [15, 17, 52].
In this study, a considerable number of patients
(71.8%) did not exhibit full recovery at the time of dis-
charge. Lack of AKI recovery in the COVID-19 setting
has been pointed out before [2, 6]. A study by Pei et al. [2]
showed that only 45.7% of patients with COVID-19 made
a complete recovery from AKI at the time of discharge.
The discrepancy seen among recovery rates may be due
to different hospital lengths of stay and follow-up in stud-
ies. This rate is significant and highly alerting that war-
rants further research to fully understand the processes of
pathophysiology and appropriate interventions to pre-
vent this complication in patients with COVID-19.
In conclusion, we demonstrated that male sex, disease
severity, previous history of CKD, hypertension, and high
serum urea level on admission are independent risk indica-
tors of AKI development during hospitalization in CO­
VID-19 patients. In addition, patients with higher stages of
AKI are at higher risk of in-hospital mortality and compli-
cations. Hence, close monitoring for serum creatinine dur-
Kidney Blood Press Res 7
DOI: 10.1159/000517581
ing hospitalization and a long-term follow-up to further
investigate CKD after COVID-19-associated AKI might be
crucial in susceptible patients with COVID-19, and more
supportive care must be considered in patients with AKI.
Limitations
Results reported in the present study should interpret
in light of the following limitations. First, this is a retro-
spective cohort study, and specific inferences regarding
the relationship between AKI and exposures cannot be
made. Second, since our population study included pa-
tients hospitalized in a single tertiary center, the extracted
data cannot represent all patients with COVID-19. Third,
according to missing data on the patient’s baseline cre-
atinine, we used the estimated creatinine method, which
is in line with several other studies done on this subject
[6, 26, 53]. Fourth, it is a single-center study on the Ira-
nian population, and future multicenter studies on differ-
ent ethnicities are needed. Fifth, due to the high burden
imposed by the disease, data regarding the patients who
undergone dialysis, need for acute renal support, and fur-
ther investigation of its risk factors could not be provided.
Statement of Ethics
This study’s protocol was in line with the 2013 Helsinki decla-
ration and was approved by the Ethics Committee of Tehran Uni-
versity of Medical Sciences (IR.TUMS.VCR.REC.1399.005). All
participants or their legal guardians gave written informed consent
before inclusion in the study.
Conflict of Interest Statement
The authors of this study declare that they have no conflict of
interest.
Funding Sources
This study has been supported by the Tehran University of
Medical Sciences (grant number: 99-1-101-47193). The funding
source had no role in the study design, data collection, data analy-
sis, data interpretation, writing of the manuscript, or decision of
submission.
Author Contributions

E.R., H.R., and H.F. contributed to the conception or design of

Acknowledgement
We acknowledge all the hardworking health-care workers in-
volved in the diagnosis and treatment of patients in Sina Hospital,
doing their best in the time of the pandemic. We are indebted to
the Research Development Center of Sina Hospital for its help and
support.
the work. S.K., H.F., H.R., F.M., and M.R. contributed to the ac-
quisition, analysis, or interpretation of data for the work. H.F.,
S.K., and F.M. drafted the manuscript. E.R., H.R., M.M., and S.K.
(2), A.S., M.T., and A.J. critically revised the manuscript. All gave
final approval and agree to be accountable for all aspects of work
ensuring integrity and accuracy.

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